The World Health Organization has ranked the breast cancer as the “leading killer” threatening to female health, and there are about 1 million female die of breast cancer each year in the world. The clinical data shows that about 80% of adult females have some degree of breast cancer in China, the morbidity rate of which is still increasing and now it has increased from 170 per million five years ago to 520 per million last year, which is more than three times higher. In recent 20 years, the morbidity rate of the breast cancer has increased around 180% in shanghai. Meanwhile, with the increasing cancer lesions, the number of women who die of breast cancer is up to 0.2 million every year, leading to disastrous panic to female health.
Now, drugs for the treatment of breast cancer mainly include: (1) chemotherapeutic drugs: such as capecitabine, docetaxel, 5-fluorouracil, doxorubicin, cyclophosphamide, paclitaxel, vinorelbine, etc.; (2) I trastuzumab and other signal transduction inhibitors: trastuzumab, clodronate, pamidronate, ibandronate, and zoledronate etc.; (3) endocrine inhibitor: tamoxifen, anastrozole, letrozole, exemestane, buserelin or goserelin, fulvestrant, and the like. Among them, most chemotherapeutic drugs have the shortage of high toxic and side effect, low improved survival, increased long term toxicity, and high cost of combined chemotherapy, etc.; I trastuzumab and other signal transduction inhibitors are most used as the adjuvant therapy of chemotherapeutic drugs. As compared to the chemotherapeutic drugs, new progress in endocrine inhibitor therapy has more important significance: tamoxifen is almost the gold standard for the endocrine therapy of breast cancer in recent 30 years, and anastrozole has potential prevention effect on breast cancer. Fulvestrant is an anti-estrogen drug. Unlike tamoxifen, fulvestrant is able to down regulate the estrogen receptor without partial agonist activity. Fulvestrant has clinical therapeutic effect in patients failed in treatment with tamoxifen. Therefore, among many drugs for treating breast cancer, fulvestrant is the only anti-estrogen agent that may be widely used in clinical treatment after the failure of tamoxifen, which has initiated a new way of treating hormone-sensitive breast cancer.
The chemical name of fulvestrant is 7-alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5-(10)-triene-3,17-beta-diol. Fulvestrant is a white or off-white powder, insoluble in water with a relative molecular weight of 606.77.
Fulvestrant is a new estrogen receptor antagonist—anti-breast cancer drugs of estrogen receptor down regulators. Currently, the main method for treatment of breast cancer is to decrease the concentration of estrogen due to estrogen receptors (ER) are found in many patients with breast cancer and the growth of tumor is stimulated by estrogen. Fulvestrant may competitively combine with estrogen receptor with the affinity similar to that of estradiol; fulvestrant may also block the receptor, inhibit its combination with the estrogen, and stimulate the receptor to have morphological changes, decrease the concentration of ER to damage the tumor cell, such effect through ER path is related to the decreasing of the cell proliferation makers, Ki67. Fulvestrant can down regulate ER protein in human breast cancer cell, and the ER is down regulated within tumor cell to minimize the growth of tumor. Because fulvestrant do not change the status of the existing tumor ER, and do not affect on the production of new ER, the tumor is continued to be “programmed” as ER positive, so that fulvestrant can continuously have a therapeutic effect. Animal experiments found that fulvestrant had no estrogen effect or anti estrogen effect of tamoxifen or the partial agonist activity on the endometrium, so its adverse effect is less than that of tamoxifen, particularly the latter has the risk of increasing the incidence rate of endometrial carcinoma.
Fulvestrant is insoluble in water causing poor oral bioavailability and being eliminated immediately after the intravenous injection. Accordingly, oral preparation and common water solution for injection are not applicable to this drug. Fulvestrant shows, along with other steroidal based compounds, certain physical properties which make formulation of these compounds difficult. Fulvestrant is a particularly lipophilic molecule, even when compared with other steroidal compounds, and its aqueous solubility is extremely low at around 10 ng/ml.
Currently there are a number of sustained release injectable steroidal formulations which have been commercialised. Commonly, these formulations use oil as a solvent, and wherein additional excipients may be present. For example, Chinese patent application CN1553815A disclosed a pharmaceutical formulation for the intramuscular administration of fulvestrant on Dec. 8, 2004, that is an oil based injection formulation of fulvestrant of AstraZeneca UK Ltd. in Sweden, which is approved by FDA on April 2002 with the trade name of Faslodex®. The solvent system of the product consists of ethanol, benzyl alcohol, benzyl benzoate, and castor oil, adapted for breech intramuscular injection, in which the content of ethanol is 10%˜20%, the content of benzyl alcohol is 10%˜20%, the content of benzyl benzoate is 15%˜50%, and the content of castor oil is 5%˜60%. All these chemical ingredients have strong irritation, and many of their adverse reactions have reported: LD50 of ethanol subcutaneous injection into mouse is 8.285g/kg, and a pain is felt when the concentration of intramuscular injection is higher than 10%. Benzyl alcohol is a colorless-transparent oily liquid with weak fragrant smell and pungent taste, the LD50 of which orally administered to rat is 1.23 g/kg. Benzyl benzoate a colorless-transparent oily liquid with faint fragrant smell, tongue contact causes a feeling of intense burning, and the LD50 of which orally administered to rat is 0.5 g/kg. Castor oil is a clear, colorless or yellowish, viscid and oily liquid with slight odour, tasteless in the first taste but later having pungent taste, and clinically is mainly used for irritant laxatives. On Dec. 20, 2004, Chinese Medicine Information News published the report titled as “Benzyl alcohol should be used cautiously for eradicating ‘frog foot disease’” on “Pharmacovigilance” column, which reported that 311 children were suffered from gluteal muscle contracture as a result of the use of benzyl alcohol as a solvent of penicillin in Zhongying township, Hefeng County of Hubei Province. On Nov. 1, 2005, Chinese Medicine Information News published the report titled as “Concerning the adverse effects caused by pharmaceutical adjuvant” on “Hot Concern” column, which indicated that ethanol was applied to many injections of the insoluble drug as a solvent, and intramuscular or subcutaneous injection of them would cause great irritation. At first, a burning sensation is caused at the injection site, severe pain, local anesthesia occurs afterwards. It can cause neurodegenerative damage when being injected near nerve carelessly. The article also indicated that, as a solvent of drug, preservatives (0.5%˜1.0%), and topical analgesics (1%˜4%), the adverse reaction of benzyl alcohol comprises hemolysis, hypotension, localized stimulus and the like. Benzyl alcohol can be bound to the surface of the red cell membrane, leading to hemolysis. It is also reported that one patient developed respiratory depression and fast hemolysis after receiving high dose of etoposide containing benzyl alcohol for treating non-hodgkin's lymphoma. Another report said that the solvent benzyl alcohol in amiodarone injection has activity of blood vessel, producing hypotension. Benzyl alcohol is also the main reason of causing gluteal muscle contracture. On Jun. 10, 2005, the State Food and Drug Administration issued “Notice on Strengthening Management of Benzyl Alcohol Injection” (No. [2005] 263 of the State Food and Drug Administration) ordered that benzyl alcohol is forbidden to use for intramuscular injection in children.
Thus, fulvestrant injection (Faslodex®) consists of the above non-aqueous chemical solvent with strong irritation which may damage the injection site. There are more than 10% of patients developing pain at the injection site in their clinical trial and the damage degree is strengthened with the increase of the dosage. After injection of Faslodex®, the non-aqueous chemical solvent is absorbed into the human muscle tissue, and then the drug is precipitated into the muscle tissue, followed by slow absorption. The release process of the drug is uncontrollable because of the rapid absorption of the non-aqueous chemical solvent by the muscle tissue, it also leads to the uncontrollability of the absorption rate of drug. More importantly, it has to use the fulvestrant oil injection with higher concentration and more non-aqueous solvent to extent the efficacy of the drug, which brings greater damage to the injection site when the fulvestrant oil injection is used for treatment in clinical in order to achieve longer time of the drug action.
Therefore, for the promising drug fulvestrant, a new formulation with no irritate to the administration site or vessel, low side effect and available for intravenous injection is needed to be developed.